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Science 16 June 2000:
Vol. 288. no. 5473, pp. 2042 - 2045
DOI: 10.1126/science.288.5473.2042
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Reports

Designing Small-Molecule Switches for Protein-Protein Interactions

Zhihong Guo, Demin Zhou, Peter G. Schultz *

Mutations introduced into human growth hormone (hGH) (Thr175 rightarrow  Gly-hGH) and the extracellular domain of the hGH receptor (Trp104 rightarrow  Gly-hGHbp) created a cavity at the protein-protein interface that resulted in binding affinity being reduced by a factor of 106. A small library of indole analogs was screened for small molecules that bind the cavity created by the mutations and restore binding affinity. The ligand 5-chloro-2-trichloromethylimidazole was found to increase the affinity of the mutant hormone for its receptor more than 1000-fold. Cell proliferation and JAK2 phosphorylation assays showed that the mutant hGH activates growth hormone signaling in the presence of added ligand. This approach may allow other protein-protein and protein-nucleic acid interactions to be switched on or off by the addition or depletion of exogenous small molecules.

Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
*   To whom correspondence should be addressed.

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